MPharm Programme Physical Stability: Polymorphic Forms PDF

MPharm Programme Physical stability: Polymorphic forms Prof. Amal Ali Elkordy Professor of Pharmaceutics Slide 1 of 23 MPharm Polymorphic forms OVERVIEW Basic crystallographic properties of crystalline and non-crystalline materials The unit cell as geometric descriptor of crystallinity Crystal latti...

MPharm Programme Physical stability: Polymorphic forms Prof. Amal Ali Elkordy Professor of Pharmaceutics Slide 1 of 23 MPharm Polymorphic forms OVERVIEW Basic crystallographic properties of crystalline and non-crystalline materials The unit cell as geometric descriptor of crystallinity Crystal lattice systems: Classification of crystal systems Crystal habit Polymorphism Crystal solvates and crystal hydrates Crystal defects – Point defects Slide 2 of 23 MPharm Polymorphic forms Polymorphic forms: Basic Crystallographic Properties of Crystalline and Non-crystalline Materials Properties of crystals: atoms and molecules are packed in a high degree of order Heat Crystals sharp transition from the solid into the liquid state (melting) Examples: sodium chloride, ibuprofen 222°C Slide 3 of 23 MPharm 230°C Polymorphic forms Properties of amorphous materials: atoms and molecules are arranged in a random order Heat Amorphous substance softening and then formation of a highly viscous liquid Examples: glass, spray-dried lactose monohydrate 231°C Slide 4 of 23 MPharm Polymorphic forms 245 °C The unit cell as geometric descriptor of crystallinity Crystallographic structure: Due to the high degree of order in crystals, a periodic reoccurrence of atoms and molecules can take place in all three dimensions in space. This crystallographic structure can be described as three-dimensional lattice, in which the unit cell is the repeating unit. Unit cell: is the building block of the crystal. Many of the building blocks packed together to fill the space of the crystal. Description of the unit cell is depend on geometry (see below). Slide 5 of 23 MPharm Polymorphic forms The unit cell as geometric descriptor of crystallinity Unit cell: described by three dimensions (the length of the axes of the unit cell and the three angles between these axes) The dimensions and angles describing a unit cell: a, b and c are lengths of axes. α, β and γ are angles between axes Slide 6 of 23 MPharm Polymorphic forms Crystal lattice systems Classification of crystal systems: - depending on geometric description, there are seven, 7, possible unit cells (basic crystal systems) that give all possible degrees of order of atoms and molecules being only at each corner of the unit cell. - Advanced crystallography classifies the crystal systems into fourteen, 14, Bravais-lattices, which consider the possibility of presence of centre atoms inside the unit cell or at edges of faces of the unit cell. Slide 7 of 23 MPharm Polymorphic forms Basic crystal lattice systems triclinic monoclinic orthorhombic trigonal hexagonal tetragonal cubic The unit cells of the seven basic crystal lattice systems Slide 8 of 23 MPharm Polymorphic forms Examples for basic crystal lattices Crystal lattices Slide 9 of 23 MPharm Proportion of axes Proportion of angles Polymorphic forms Example Crystal habit - describes the overall shape of the crystal - results of different rates of growth in each dimension Two crystals (orthorombic) with same habit may have different combinations of faces. Crystals with same combinations of crystallographic forms may have different crystal habits: a- prismatic, b- isometric, c- tabular Slide 10 of 23 MPharm Polymorphic forms (Florence and Attwood, 2006) a b c Crystal habit modification - Crystal habit can be modified by adding impurities - Example: Presence of surfactants, in the crystallisation solution, can change crystal habit by adsorbing onto crystal faces during crystal growth e.g. influence of anionic and cationic surfactants on crystal habit of adipic acid. - Anionic surfactant results in thin long needle Slide 11 of 23 MPharm Polymorphic forms - Cationic surfactant results in thin flaky plates Polymorphism - Polymorphic substance can form crystal forms with different order of molecules or atoms - for the inner order, not for the crystal shape - Polymorphic forms can have same type of crystal lattice (e.g. triclinic) however different proportions of axes and angles - Because polymorphic forms have different order of elements, therefore there will be different attraction forces to join molecules. Accordingly, different polymorphs will: Slide 12 of 23 MPharm Polymorphic forms Polymorphism - have different thermodynamic stability - have different free energies - have different fundamental physical properties: (melting point, vapour pressure, solubility) - have effect on the manufacture of dosage forms - have effect on pharmacological activity of dosage forms - have effect on drug bioavailability Slide 13 of 23 MPharm Polymorphic forms Effect of polymorphic forms on bioavailability of chloramphenicol palmitate (Florence and Attwood, 2006) Slide 14 of 23 MPharm Polymorphic forms Transition between polymorphic forms - by heat or pressure - “enantropic transition”: transition between all forms - “monotropic transition”: transition from one form to another and not vice versa in other words: transition from metastable form into stable form; metastable forms are higher energy polymorphs - stable polymorphic form has: - lowest free energy - highest melting point - usually, lowest solubility. Slide 15 of 23 MPharm Polymorphic forms Transition between polymorphic forms - Nomenclature of polymorphic forms: Roman numbers (I, II,….etc), in the order of highest melting point - Example: testosterone - polymorphic form I: stable form (MP=155°C) - Polymorphic forms II-IV: metastable forms (MP=148, 144 and 143°C, respectively) - in drug delivery, it is better to have metastable forms; they have better solubility, they give better dissolution and bioavaialbility (see the previous Figure) Slide 16 of 23 MPharm Polymorphic forms Polymorphism of paracetamol Polymorph I (monoclinic) Polymorph II (orthorombic) (Florence and Attwood, 2006) Polymorph I &II at room temperature Slide 17 of 23 MPharm Polymorphic forms Polymorph I after 30 min Crystal solvates and crystal hydrates - during crystallisation, some materials may entrap solvent in the crystal: - Crystal solvates: crystals contain solvent of crystallisation - Crystal hydrates: water is the solvent of crystallisation - Anhydrates: crystals with no water of crystallisation - polymorphic solvate: solvent interact with crystal structure (bonding); when crystals lose the solvent, a new crystal form will be produced Slide 18 of 23 MPharm Polymorphic forms Crystal solvates and crystal hydrates - pseudopolymorphic solvate: no interaction between the solvent and crystal bonding; when crystal solvates lose the solvent, crystal lattice will not be destroyed - crystal hydrate and anhydrate of a drug have different solubility and melting point and hence different pharmaceutical properties - hydrates are less soluble and thermodynamically more stable Slide 19 of 23 MPharm Polymorphic forms Bioavailability of ampicillin in anhydrate and trihydrate forms (Florence and Attwood, 2006) Slide 20 of 23 MPharm Polymorphic forms Crystal defects – Point defects - Due to: - impurity replacing the original atom - defect can influence the physical properties of the crystals - missing atom Slide 21 of 23 MPharm Polymorphic forms Summary - Understanding the meaning of unit cell and crystal lattice - knowledge about crystal habit and polymorphism - ability to differentiate between crystal hydrates and solvates Slide 22 of 23 MPharm Polymorphic forms Recommended reading - Particle Science and Powder Technology, Part 2 (2017). In: Aulton, M.E., Taylor K.M.G (eds.), Aulton’s Pharmaceutics, The Design and Manufacture of Medicines. 5th Ed., Elsevier Publisher, pages: 129-137. - Florence A.T., Attwood, D., 2006. Physicochemical Principles of Pharmacy. 4th Edition, Pharmaceutical Press, London, pp. 8-22. Slide 23 of 23 MPharm Polymorphic forms THANK YOU FOR YOUR ATTENTION MPharm Polymorphic forms